Tumor cell -TAM Paracrine Signaling in Breast Cancer

乳腺癌中的肿瘤细胞 -TAM 旁分泌信号传导

• 批准号: 10583793
• 负责人: Elizabeth S. Yeh
• 金额: $ 45.64万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-13 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10583793
• 关键词: 4T1; Affect; Agonist; Antineoplastic Agents; Attenuated; Back; Breast Cancer Model; Breast Cancer cell line; Categories; Cells; Chemoresistance; Clinical; Data; Diagnosis; Disease; Down-Regulation; Endowment; Epidermal Growth Factor Receptor; Exhibits; Extracellular Matrix; FDA approved; Flow Cytometry; Genetic Transcription; Goals; Grant; Human; Immune; Immune checkpoint inhibitor; Immunohistochemistry; Immunosuppression; Impairment; Individual; Infiltration; Inflammatory; Interleukin 4 Receptor; Interleukin 6 Receptor; Interleukin-4; Invaded; Knowledge; Lymphocytic Infiltrate; Macrophage; Macrophage Activation; Mammary Neoplasms; Measures; Mediating; Methods; Modeling; Neoplasm Metastasis; Paracrine Communication; Patients; Phenotype; Phosphorylation; Phosphotransferases; Play; Population; Primary Neoplasm; Production; Prognosis; Receptor Signaling; Recovery; Regulation; Research; Role; Sampling; Shapes; Signal Pathway; Signal Transduction; Stat3 Signaling Pathway; Testing; Time; Tumor Angiogenesis; Tumor Biology; Tumor Promotion; Tumor-Infiltrating Lymphocytes; Tumor-associated macrophages; Up-Regulation; Work; antitumor effect; cell type; improved; in vivo; in vivo Model; knock-down; loss of function; malignant breast neoplasm; mammary; mouse model; neoplastic cell; paracrine; recruit; response; single-cell RNA sequencing; small hairpin RNA; therapeutic evaluation; transcription factor; triple-negative invasive breast carcinoma; tumor; tumor microenvironment; tumorigenic

ABSTRACT Immune checkpoint inhibitors are FDA approved for metastatic triple negative breast cancer (TNBC) and work well for patients with high levels of tumor infiltrating lymphocytes (TIL), but for the majority of BC patients, these agents are ineffective. Continued research is needed to elucidate the interplay between tumor cells and the diverse immune cell populations within the primary TME, and how this interaction shapes tumor biology. Tumor- associated macrophages (TAM) represent one of the most abundant immune components in BC TME and exhibit a robust and unique influence on the disease. High levels of TAM infiltration are associated with poor prognosis in BC. TAMs play a critical role in a wide range of pro-tumorigenic, pro-metastatic activities including tumor angiogenesis, extracellular matrix (ECM) remodeling, immunosuppression, and chemoresistance. How to surmount TAM infiltration and function in order to activate a potent anti-tumorigenic and anti-metastatic response represents a gap in knowledge for the BC field. TAMs most closely resemble M2-polarized type macrophages and exhibit some overlapping functions between the categories. TAMs are a highly heterogeneic, plastic cell population endowed with tumor-promoting functionality measured by the overall abundance of M2 vs M1 markers. TAM polarization and immunosuppressive capacities are dependent upon where these cells are located and what signals are received within the TME. Whereas M2-like polarization is considered pro-tumorigenic, M1- like polarization is associated with inflammatory, anti-tumor effects and improved prognosis. Tumor cells generate paracrine signals that recruit and regulate TAM function. In turn, TAMs produce signals that affect the metastatic potential of tumor cells. Given the clear pro-tumor and metastatic roles of TAMs, it seems evident that identifying ways to abrogate pro-tumorigenic M2-like responses and promote anti-tumorigenic M1-like responses in BC will be clinically advantageous. However, effective strategies remain elusive. Our proposal introduces a new strategy to target a kinase called HUNK that has the potential to be more advantageous than strategies that directly target TAMs. Targeting HUNK will have a multifaceted effect by not only halting pro-tumor/metastatic tumor intrinsic signaling but also fundamentally changing the “feed forward” paracrine loop between tumor cells and TAMs.

抽象的 免疫检查点抑制剂已获得FDA批准用于转移性三重阴性乳腺癌（TNBC）和工作 对于高肿瘤浸润淋巴细胞（TIL）的患者，但对于大多数卑诗省患者， 药物无效。需要继续研究以阐明肿瘤细胞与 原发性TME中的不同免疫菌株种群，以及这种相互作用如何塑造肿瘤生物学。瘤- 相关的巨噬细胞（TAM）代表BC TME中最丰富的免疫成分之一 对疾病的强大而独特的影响。高水平的TAM浸润与预后不良有关 在卑诗省。 TAMS在多种亲抗肿瘤的亲抗物活动中起着至关重要的作用，包括肿瘤 血管生成，细胞外基质（ECM）重塑，免疫抑制和化学抗性。如何 超越TAM浸润和功能，以激活潜在的抗肿瘤和抗转移性反应 代表BC领域知识的差距。 TAM最类似于M2极化型巨噬细胞 并暴露了类别之间的一些重叠功能。 TAM是一个高度异质的塑料细胞 通过M2和M1的总体抽象来衡量的肿瘤促进功能的种群 标记。 TAM极化和免疫抑制能力取决于这些细胞的位置 以及在TME中收到的信号。而M2样极化被认为是阳离子的M1- 就像极化一样，与炎症，抗肿瘤作用和预后改善有关。肿瘤细胞 生成募集和调节TAM功能的旁分泌信号。反过来，TAM产生了影响该信号的信号 肿瘤细胞的转移潜力。鉴于TAM的明确肿瘤和转移性作用，似乎证据表明 确定废除促肿瘤的M2样反应并促进抗肿瘤M1样反应的方法 在卑诗省将在临床上有利。但是，有效的策略仍然难以捉摸。我们的建议介绍了 针对一种称为Hunk的激酶的新策略，该激酶有可能比策略更有优势 直接靶向TAM。靶向大块 肿瘤内在信号传导，但也从根本上改变了肿瘤细胞之间的“前馈”旁分泌环 和tams。